Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has given rise to new variants: viruses with different sets of mutations, some of which have increased transmissibility and immune escape. Detecting and monitoring new variants was made possible by intensive, global genomic surveillance efforts, including sequencing over 1.2 million SARS-CoV-2 genomes in the first pandemic year. Crucial to these efforts was the Rapid Acceleration of Diagnostics (RADx®) Variant Task Force, which was established in 2021 to monitor variants and assess the efficacy of RADx technologies against new variants. Major accomplishments of the RADx Variant Task Force include the establishment of the ROSALIND Diagnostic Monitoring system to identify mutations, the creation of an extensive biobank of sequenced samples, laboratory testing of RADx technologies against new variants as they emerged, and epitope mapping to identify mutations likely to affect an assay’s performance. Key lessons learned include (1) the need for very early establishment of pathogen sequencing, analysis, and data sharing; (2) the importance of both in silico and wet laboratory assessment of diagnostic assays; and (3) the benefits of interdisciplinary collaboration of government, academia, and industry.